When Robert Hughes started his anti-HIV treatment back in the early 1990s, his best hope of survival was a single drug called AZT. It helped at first, but the virus soon adapted to the treatment--and went back to destroying his immune system. Today there are 25 drugs in the anti-HIV arsenal, and the 42-year-old New Yorker is holding his ground with a four-drug cocktail that includes a costly new lifesaver called enfuvirtide (Fuzeon). But the race against the AIDS virus is far from finished. As one major study concluded recently, "a substantial proportion of [treated] patients seem to be in danger of exhausting their options for antiretroviral treatment."

HIV infection was essentially a death sentence until 1996, when researchers developed regimens that could hit the virus from three angles at once. The three-drug cocktails combined compounds like AZT (which help keep HIV from infiltrating the host cell's chromosomes) with newer ones called protease inhibitors, which can keep infected cells from producing new copies of the virus. These three-drug cocktails still work well when people adhere to them perfectly and stick with them for life. But few patients can meet that standard--and any change or interruption in treatment can foster drug resistance. Ricardo Flores, a 46-year-old Californian, ended up in treatment failure after depression sapped his motivation to take his pills. For Devin, a 27-year-old North Carolina woman who prefers not to use her last name, the drugs' own side effects were the biggest obstacle to adherence. "I couldn't even eat without getting nauseous and having diarrhea," she says.

Like Hughes, Flores and Devin got a break two years ago when Roche Pharmaceuticals introduced Fuzeon, the first (and still the only) member of a new class of drugs called entry inhibitors. Unlike earlier treatments, which attack HIV from inside infected cells, entry inhibitors work by blocking HIV at the gate--as it tries to penetrate the cell's outer membrane. When failing patients combine the new drug with the older ones that still have some effect, the results can be dramatic. Devin has seen a sharp decline in her viral load (the amount of HIV in her blood), and an increase in her CD4 cells, the body's linebackers against illness. "It's a godsend," she says.

Perhaps, but it's no panacea. Other anti-retrovirals can be taken orally, but patients have to inject Fuzeon on a strict, 12-hour schedule. The drug's side effects can range from constipation to sleeplessness and depression. And the cost can top $20,000 a year. Fortunately, treatment-resistant patients could soon have a range of other options, some of which may come in pill form. Pfizer, GlaxoSmithKline, Schering-Plough, AnorMED and Progenics all have entry inhibitors in clinical trials and are hoping to seek FDA approval within the next few years. "[Entry inhibitors] are the next wave," says Dr. Lisa Dunkle, a scientist at Schering-Plough pharmaceuticals.

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For now, patients like Hughes can only hope their luck holds out until newer, better treatments reach the clinic. Fuzeon has kept his viral load low for more than a year, and the side effects he had been experiencing, such as vomiting, have subsided. But he's ridden this roller coaster before. His hope is simply to keep it on the track.